Diabetes mellitus is a severe disorder that affects more and more human in the world. The forecast of International Diabetes Federation alludes that the total worldwide number of human with diabetes mellitus will be 380,000,000 (three hundred eighty million) until 2025. The attack rate of diabetes mellitus is increasing along with a growing tendency of obesity in many countries. The severe effect of diabetes mellitus includes the increased risk of stroke, heart disease, kidney failure, blindness and amputation. Cardiovascular disorders are more than 70% leading cause of all death in human with Type II diabetes (T2DM) [B. Pourcet et al. Expert Opin. Emerging Drugs 2006, 11, 379-401].
Diabetes mellitus is characterized in the insulin secretion and/or the disturbance of insulin signal reaction in peripheral tissues. There are two types' diabetes mellitus, that is, insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus. Most of the patients with diabetes mellitus are suffering from non-insulin-dependent diabetes mellitus, which is known as Type II diabetes or NIDDM. Because of the severe consequence of diabetes mellitus, the control of diabetes mellitus is necessary desperately.
The treatment of NIDDM generally begins weight loss, healthy diet and exercise program. Although these factors are important especially to dissolve the increased risk of cardiovascular disorders related to diabetes mellitus, they are not effective generally for the control of diabetes mellitus itself. There are many drugs useful for the treatment of diabetes mellitus, including insulin, metformin, sulfonylureas, acarbose, thiazolidinedione, GLP-1 analogue and DPP IV inhibitor. However, some of such treatment agents have a problem including more than one disadvantage of hypoglycemic episodes, weight gain, gastrointestinal problems and loss in responsiveness to therapy over time.
Although many medicines for the treatment of diabetes mellitus through the various mechanisms are approved, lots of medicines still are under clinical appraisal, and there still is need to develop novel compound for the treatment of diabetes mellitus. Recently, the research result showing the observation that beta-cell function of diabetes patient declines over time regardless of success or failure of treatment with diet, sulfonylureas, metformin or insulin has been published [R. R. Holman Metabolism 2006, 55, S2-S5].
GPR119 is a protein consisted of 335 amino acids expressed in beta-cell of pancreatic islet [Z.-L. Chu et al., Endocrinol. 2007, J 48, 2601-2609] and gastro-intestinal tract [Z.-L. Chu et. al., Endocrinol. 2008, 149, 2038-2047]. Said protein belongs to the receptor family coupled to G-protein, and some candidates including oleoylethanolamide (OEA), N-oleoyldopamine and olvanil are suggested as intrinsic ligand [H. A. Overton et al. Brit. J. Pharmacol. 2008, 153, S76-81].
It is supported from many research using cell line and animal that GPR119 may perform a certain function in glucose-dependent secretion of insulin, and targeting to GPR119 receptor may be effective to the treatment of diabetes mellitus. Activation of GPR119 receptor by lisophosphatidilcholine forces up the glucose-dependent secretion in the pancreas beta-cell line of mice, and the insulin secretion can be blocked by GPR119-specific siRNA [T. Soga et al. Biochem. Biophys. Res. Commun. 2005, 326]
Therefore, GPR119 receptor activator is needed for the treatment of disorders, such as diabetes mellitus.